We are using genetic strategies to locate genes responsible for alcoholism-associated behavioral differences in humans and animals. The research involves searching for non-random assortment or association of markers and genetic behavioral phenotypes. The probability of establishing linkage or an association is being maximized by 1) focusing on human alcoholism with impulsivity/aggressivity as a prominent accompanying behavioral trait 2) using primate and rodent genetic models and 3) using a large panel of polymorphisms. Markers include DNA probes we are cloning for the specific study of the Y chromosome. Also, we are mapping new protein polymorphisms by two-dimensional electrophoresis. Using this technique, we have demonstrated 30 polymorphic protein markers in cultured fibroblasts and from serum and erythrocytes. We have identified two of these loci, phosphoglucomutase-3 and glyoxalase 1, and the identities of 10 other loci are also known. Our population studies have shown that the minimum level of human protein heterozygosity (genetic variability) is approximately 2.5% compared to lower levels of average protein heterozygosity in two endangered species with lowered genetic variation, the cheetah and the giant panda. In human studies, we are collecting fibroblast and lymphoblast cell lines from impulsive and nonimpulsive alcoholic males to provide a resource for testing genetic markers and for in vitro metabolic studies. In rodent studies, we have mapped 12 genetically variant brain protein loci. We are attempting to correlate these genetic brain molecular differences with a genetic behavioral difference, sleep time after a dose of ethanol. In studies involving primates and rodents, we are trying to better localize and characterize the expression in brain of alcohol and aldehyde dehydrogenases, the principal enzymes involved in the metabolism of ethanol.